Effective treatment of diseases such as cancer require robust immune responses by one or more effector cell types such as natural killer (NK) cells, macrophage and T lymphocytes. In animals and patients bearing tumors, the immune system has not effectively dealt with the growing tumor due, in large part, to specific mechanisms the tumor has elaborated to suppress the immune response. In many cases, potentially tumor-destructive monocytic cells, e.g. macrophages, migrate into growing tumor beds, but the secretion of factors such as prostaglandins, TGF-β and IL-10 by the tumor cells modulate their cytotoxic activity (see, for example, Sharma et al., 1999, J. IMMUNOL. 163:5020-5028). Likewise, lymphocytic cells migrating into tumors, such as NK and T cells, can be suppressed by factors secreted by tumors as well as by interactions with receptors expressed on the surface of tumor cells that activate apoptosis of the immune cells (see, for example, Villunger, et al, 1997, BLOOD 90:12-20). The exposure of these lymphocytes to immunosuppressive monocytic cells within the tumor bed can further reduce their ability to mount an effective anti-tumor response.
Efforts made to overcome the immune suppressive effects of the local tumor microenvironment include targeted immune stimulation, such as treatment with tumor-specific antibody-cytokine fusion proteins. Effective treatment with this approach has been demonstrated in several mouse tumor metastasis models, however, treatment is far less effective as the size of the tumors increases. This is likely due to the increased level of suppressive factors secreted by the tumor mass as well as other factors, such as the increase in tumor interstitial fluid pressure (Griffon-Etienne et al. 1999, CANCER RES. 59:3776-3782), a barrier to penetration of solid tumors by therapeutic agents.
While most cancer patients are still treated with one or more courses of chemotherapy, it is well known that cytotoxic therapy of cancer is damaging to the immune system. Immune cells are among the most rapidly dividing cells in the human body, and any treatment that kills dividing cells will also kill immune cells. Thus, treatments including radiation, DNA-damaging chemicals, inhibitors of DNA synthesis, and inhibitors of microtubule function all cause damage to the immune system. Bone marrow transplants are needed as an adjunct to cancer therapy precisely because the immune system becomes damaged and needs to be replenished. Methotrexate and other anti-cancer drugs are often used as immunosuppressants. There is also evidence that anti-cancer treatments can specifically inhibit T cell function. For example, patients who have been treated for Hodgkin's disease with whole-body irradiation suffer from an apparently permanent loss of naïve T cells (Watanabe et al., 1997, Blood 90:3662).
Based on current knowledge it would appear unlikely that standard treatments (chemotherapy and radiation) and local immune stimulation would be a useful combination approach for effective treatment of cancer. Therefore, there is a need in the art for methods that enhance antibody-cytokine fusion protein mediated immune responses against pre-selected cell types, for example, tumor cells, and compositions employed in such methods.